Several overall objectives of the proposed research may be stated: (1) An improved understanding of the role of cyclic-3', 5'-nucleoside monophosphates in cell processes, especially those affecting malignant transformation; (2) increased knowledge of the role of electronic and steric effects on the conformations of the cyclophosphamide ring system and of conformation on cytostatic activity; (3) synthetic utilization of the free-radical chemistry of pentacovalent phosphorus compounds containing the PH bond. Synthetic methods based on isolated cyclic nucleotide analogs featuring trivalent phosphorus will be used to prepare a large number of neutral, derivatized cyclic nucleotides with new functionality at phosphorus. NMR methods will be used to assign molecular geometry to diastereoisomers. Geometry will be related to biological activity, including cytotoxicity, in enzyme, whole cell and in vivo systems. Basic conformational properties of the cyclophosphamide ring system will be determined and related to ease of microsomal activation and detoxification as well as to cytotoxic activity. The potentially general photo and thermal initiated free radical functionalization of a variety of pentacovalent phosphorus compounds containing the PH bond will be investigated.